The present invention relates to a production method of an optically active naphthalene derivative having a pharmacological action, particularly a steroid C17,20-lyase inhibitory activity, a reagent for optical resolution thereof and a production method of the reagent for optical resolution. More specifically, the present invention relates to a production method of naphthalene derivatives which comprises use of an optically active cyclic phosphorus compound as a reagent for optical resolution, a salt formed during the optical resolution, a novel optically active dioxaphosphorinan useful as a reagent for optical resolution, a reagent for optical resolution containing a novel optically active dioxaphosphorinan and a production method of the reagent for optical resolution.
Since chemically synthesized naphthalene derivatives represented by the formula (I) have an asymmetric carbon and have two kinds of optical isomers, there is a demand for a technique to selectively and efficiently prepare an optically active form thereof. For the production of an optically active amino compound, it is a general practice to use what is called a diastereomer salt method which comprises reacting an optically active acid compound with an amino compound (racemate) and separating the resulting salt mixture based on differences in the physical properties. For use of this method, various optically active acidic compounds have been developed and utilized as reagents for optical resolution (Separation Purification Technique Handbook, The Chemical Society of Japan, Maruzen, p. 459 (1993)).
Some of the optically active compounds represented by the formula (II) can be prepared according to the method described in JP-A-61-103886 and the like and are used for the optical resolution of amino acids, such as p-hydroxyphenyl glycine and phenylalanine, and amino compounds, such as 1-phenyl-2-paramethoxyphenyl-ethylamine and 1,2-di(4xe2x80x2-chlorophenyl)-1,2-diamino-ethane.
An optically active compound represented by the formula (III) can be produced according to the method described in JP-B-55-47013 and the like and is used as a reagent for the resolution of amino acids such as adrenaline, lysine, glutamic acid and the like, amphetamines, basic antibiotics such as lincomycin, tetracycline and the like, atropine, scopolamine, catecholamine, ephedrine, morphine, phenothiazines, perhexilin, prostaglandins and intermediates therefor, xcex1-p-ethoxyphenylamino-N-n-propyl-propionamide, xcex1,xcex1-diphenyl-xcex1-(2-piperidine)methanol, DOPA and many other amines.
Of the reagents for optical resolution of amino compounds, an optically active dioxaphosphorinan described in The Journal of Organic Chemistry, Vol. 50, p. 4508 (1985) and JP-A-61-103886 shows relatively high efficiency of optical resolution and can be derived easily. Therefore, it characteristically permits selection of a preferable one from various reagents for optical resolution.
As a production method of an optically active dioxaphosphorinan, a method comprising optical resolution of a racemate of dioxaphosphorinan is disclosed in the above-mentioned publications.
On the other hand, what is called an asymmetric synthetic method, wherein an optically active compound is directly produced without relying on optical resolution, is remarkably progressing in recent years. For synthesis of an optically active hydroxyester compound, for example, asymmetric hydrogenation using a rutheniumxe2x80x942,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl (abbreviated as BINAP) complex (Journal of the American Chemical Society, Vol. 109, p. 5856 (1987), asymmetric hydrogenation using 1,2-bis(tert-butylmethylphosphino)ethane (abbreviated as BisP*) (Tetrahedron Letters, Vol. 40, p. 2577 (1999)), and asymmetric hydrogenation using 1,2-bis(trans-2,5-diisopropylphosphorano)ethane (abbreviated as i-Pr-BPE) (Journal of the American Chemical Society, Vol. 117, p. 4423 (1995)) are known.
While an optically active dioxaphosphorinan shows a relatively high resolution efficiency and versatility as a reagent for optical resolution, it is frequently found to be unsuitable for optical resolution of an intermediate for a pharmaceutical product having a complicated chemical structure.
According to a method disclosed for the synthesis of optically active dioxaphosphorinan, dioxaphosphorinan as a racemate is optically resolved by a diastereomer salt method. Therefore, its theoretical yield does not exceed 50%. Moreover, this method requires an optically active amine in an equivalent amount as a reagent for optical resolution, but the optically active amine is not necessarily easily available. Thus, this method is not economically advantageous.
The present invention provides a method for producing (R) or (S)-(I) having a high optical purity by efficient optical resolution of a mixture of optical isomers of a naphthalene derivative represented by the formula (I), a general-purpose reagent for optical resolution, which is superior in resolution efficiency, and a method for producing the resolution reagent in a high yield and in an industrially advantageous manner.
The present inventors have found that the above-mentioned objects can be achieved by converting optical isomers of a naphthalene derivative represented by the formula (I) in a mixture to diastereomer salts with an optically active acidic compound and separating the salts, and intensively investigated further to complete the present invention.
Accordingly, the present invention relates to
(1) a production method of an optically active form of a compound represented by the formula: 
xe2x80x83wherein R is a nitrogen-containing heterocyclic group optionally having substituents, R1 is a hydrogen atom, a hydrocarbon group optionally having substituents, or a aromatic heteromonocyclic group optionally having substituents, R2 is a hydrogen atom or a lower alkyl group optionally having substituents, * shows the position of an asymmetric carbon, R3, R4, R5, R6, R7, R8 and R9 are each independently a hydrogen atom, a hydrocarbon group optionally having substituents, a hydroxy group optionally having substituents, a thiol group optionally having substituents, an amino group optionally having substituents, an acyl group or a halogen atom, and R7 may be bonded with R6 or R8 to form, together with a carbon atom on a naphthalene ring, a 5 or 6-membered ring containing an oxygen atom, or a salt thereof, which comprises reacting a mixture of optically active compounds of the naphthalene derivative represented by the formula (I) with an optically active form of a compound represented by the formula: 
xe2x80x83wherein ring A is a benzene ring optionally having substituents, R10 and R11 are the same or different and each is a hydrogen atom, a hydrocarbon group optionally having substituents or a halogen atom, or R10 and R11 in combination represent an alkylene group optionally having substituents, and * shows the position of an asymmetric carbon, or an optically active form of a compound represented by the formula: 
xe2x80x83wherein ring B and ring C are each an aromatic ring optionally having substituents, separating the resulting salt and isolating an optically active form,
(2) the production method according to the above-mentioned (1), wherein the nitrogen-containing heterocyclic group optionally having substituents, which is represented by R, is an imidazolyl group optionally having substituents, a thiazolyl group optionally having substituents, an oxazolyl group optionally having substituents or a pyridyl group optionally having substituents,
(3) the production method according to the above-mentioned (1), wherein the nitrogen-containing heterocyclic group optionally having substituents, which is represented by R, is a 4 or 5-imidazolyl group optionally having substituents or a 3 or 4-pyridyl group optionally having substituents,
(4) the production method according to the above-mentioned (1), wherein, when the nitrogen-containing heterocyclic group optionally having substituents, which is represented by R, is an oxazolyl group optionally having substituents or a thiazolyl group optionally having substituents, R1 is a saturated hydrocarbon group optionally having substituents, when R is a pyridyl group and either R1 or R2 is a hydrogen atom, R7 is a hydroxy group optionally having substituents or a lower alkyl group optionally having substituents, and when R is an oxazolyl optionally having substituents and R1 is a hydrogen atom, R2 is a lower alkyl group optionally having substituents,
(5) the production method according to the above-mentioned (1) or (4), wherein R1 is a hydrogen atom, a lower alkyl group optionally having substituents, a lower alkenyl group optionally having substituents, a cyclic alkyl group optionally having substituents or a phenyl group optionally having substituents,
(6) the production method according to the above-mentioned (1) or (4), wherein R1 is a lower alkyl group,
(7) the production method according to the above-mentioned (1) or (4), wherein R2 is a hydrogen atom or a lower alkyl group,
(8) the production method according to the above-mentioned (1) or (4), wherein R1 is a C1-6 alkyl group and R2 is a hydrogen atom,
(9) the production method according to the above-mentioned (1) or (4), wherein R3, R4, R5, R6, R7, R8 and R9 are each independently a hydrogen atom, a hydrocarbon group optionally having substituents, a hydroxy group optionally having substituents, an amino group optionally having substituents or an acyl group,
(10) the production method according to the above-mentioned (1) or (4), wherein 1 to 3 of R3, R4, R5, R6, R7, R8 and R9 are each independently a hydrogen atom, a hydrocarbon group optionally having substituents, a hydroxy group optionally having substituents or an acyl group,
(11) the production method according to the above-mentioned (1) or (4), wherein R7 is [1] a hydroxy group optionally having, as a substituent, a lower alkanoyl group, a lower alkanoyloxy(lower)alkyl group, a lower alkyl group, a lower alkoxy(lower)alkyl group, a lower alkyl group optionally substituted by 1 to 4 fluorine atoms, or a benzyl group, [2] a halogen atom, [3] a lower alkyl group optionally substituted by a hydroxy group, [4] a lower alkynyl group, [5] a lower alkanoyl group, [6] amino group optionally having a lower alkanoyl group, a lower alkylaminocarbonyl group or a lower alkylsulfonyl group as a substituent, [7] a lower alkylthio group or [8] a carbamoyl group optionally having substituents,
(12) the production method according to the above-mentioned (1) or (4), wherein R7 is a lower alkyl group, a hydroxy group optionally having substituents, a lower alkanoylamino group, or a carbamoyl group optionally having substituents,
(13) the production method according to the above-mentioned (1) or (4), wherein R8 is a hydrogen atom, a lower alkyl group or a lower alkoxy,
(14) the production method according to the above-mentioned (1) or (4), wherein R6 is [1] a hydrogen atom, [2] a halogen atom, [3] a lower alkoxy group or [4] a lower alkyl group optionally substituted by a hydroxy group,
(15) the production method according to the above-mentioned (1) or (4), wherein either R6, R7 or R8 is a lower alkyl group or a lower alkoxy group,
(16) the production method according to the above-mentioned (1) or (4), wherein R3, R4, R5 and R9 are a hydrogen atom,
(17) the production method according to the above-mentioned (1) or (4), wherein R7 is a methylcarbamoyl and R3, R4, R5, R6, R7, R8 and R9 are a hydrogen atom,
(18) the production method according to the above-mentioned (1) or (4), wherein the naphthalene derivative represented by the formula (I) is 1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol, 1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol, 1-(6-methoxy-5-methylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol, N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamide, N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl-2-naphthamide, N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide or N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-3-methylbutyl]-N-methyl-2-naphthamide,
(19) the production method according to the above-mentioned (1) or (4), wherein a compound represented by the formula (I) and an optically active form of a compound represented by the formula (II) are reacted,
(20) the production method according to the above-mentioned (19) wherein the compound represented by the formula (II) is a compound represented by the formula: 
xe2x80x83wherein ring A and * mean as defined above, and Alk is a C2-4 alkylene optionally having substituents,
(21) the production method according to the above-mentioned (20) wherein the compound represented by the formula (IIa) is a compound represented by the formula: 
xe2x80x83wherein * means as defined above,
(22) a salt of an optically active compound represented by the formula: 
xe2x80x83wherein Q1 is an optically active form of a compound represented by the formula: 
xe2x80x83wherein R10 and R11 are the same or different and each is a hydrogen atom, a hydrocarbon group optionally having substituents or a halogen atom, or R10 and R11 in combination represent an alkylene group optionally having substituents and ring A is as defined above, or an optically active form of a compound represented by the formula: 
xe2x80x83wherein each symbol is as defined above,
(23) a salt of an optically active compound represented by the formula: 
xe2x80x83wherein Q2 is an optically active form of a compound represented by the formula: 
xe2x80x83wherein ring B and ring C are each as defined above, or an optically active form of a compound represented by the formula: 
xe2x80x83wherein each symbol is as defined above, and other symbols are as defined above,
(24) a salt represented by the formula: 
xe2x80x83a salt represented by the formula: 
xe2x80x83a salt represented by the formula: 
xe2x80x83a salt represented by the formula: 
xe2x80x83or a salt represented by the formula: 
(25) a compound represented by the formula (IIa) or a salt thereof,
(26) the compound of the above-mentioned (25), which is an optically active form,
(27) a production method of an optically active form of a compound represented by the formula (II), or a salt thereof, which comprises subjecting a compound represented by the formula: 
xe2x80x83wherein R12 is a hydrogen atom, a lower alkyl group optionally having substituents or an aryl group optionally having substituents, and other symbols are as defined above, or a salt thereof, to an asymmetric hydrogenation reaction, reducing an optically active form of the obtained compound represented by the formula; 
xe2x80x83wherein each symbol is as defined above, or a salt thereof, and subjecting an optically active form of the obtained compound represented by the formula: 
xe2x80x83wherein each symbol is as defined above, or a salt thereof, to phosphorylation,
(28) the production method according to the above-mentioned (27), wherein the asymmetric hydrogenation reaction is carried out in the presence of a ruthenium complex with an optically active compound represented by the formula: 
xe2x80x83wherein R13 and R14 are different and each is a hydrocarbon group optionally having substituents or a heterocyclic ring optionally having substituents, and * means as defined above, or a salt thereof, and
(29) a reagent for optical resolution which comprises an optically active form of a compound represented by the formula (IIa) or a salt thereof.
In the above-mentioned formulas, the xe2x80x9cnitrogen-containing heterocyclic groupxe2x80x9d of the xe2x80x9cnitrogen-containing heterocyclic group optionally having substituentsxe2x80x9d represented by R is exemplified by a nitrogen-containing aromatic heterocyclic group or a saturated or an unsaturated nitrogen-containing non-aromatic heterocyclic group (nitrogen-containing aliphatic heterocyclic group), having, as an atom (ring atom) constituting the ring, at least one nitrogen atom, which is preferably a nitrogen-containing aromatic heterocyclic group. Examples of the nitrogen-containing aromatic heterocyclic group include 5 or 6-membered nitrogen-containing aromatic heterocyclic group such as imidazolyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl and 1,2,4-triazinyl. Of these, imidazolyl, pyridyl, thiazolyl, oxazolyl and the like, particularly 4 or 5-imidazolyl group and 3 or 4-pyridyl group, are preferable.
The substituent of the xe2x80x9cnitrogen-containing aromatic heterocyclic group optionally having substituentsxe2x80x9d represented by R may be present in the number of 1 to 3 at substitutable positions of the nitrogen-containing aromatic heterocyclic group. Examples of the substituent include lower alkyl group, lower alkoxy group, acyl group and the like, which optionally have substituents. Examples of the xe2x80x9clower alkyl group optionally having substituentsxe2x80x9d include non-substituted C2-4 alkyl group such as methyl, ethyl, propyl and the like, such alkyl group substituted by C1-6 alkanoyl (e.g., acetyl, propionyl etc.), carboxyl, C1-4 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl etc.) and the like. Examples of the xe2x80x9clower alkoxy groupxe2x80x9d include C1-3 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy and the like.
Examples of the xe2x80x9cacyl groupxe2x80x9d include alkanoyl group (e.g., C1-6 alkanoyl such as formyl, acetyl, propionyl etc.), alkylsulfonyl group (e.g., C1-4 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl etc.), arylsulfonyl group (e.g., benzenesulfonyl, p-toluenesulfonyl etc.), carbamoyl group optionally having substituents (e.g., mono- or di-C1-10 alkylcarbamoyl group such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl etc., mono- or di-C6-14 arylcarbamoyl such as phenylcarbamoyl, diphenylcarbamoyl etc., mono- or di-C7-16 aralkylcarbamoyl group such as benzylcarbamoyl, dibenzylcarbamoyl etc., and the like), sulfamoyl group optionally having substituents (e.g., mono- or di-C1-10 alkylsulfamoyl group such as methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl etc., mono- or di-C6-14 arylsulfamoyl group such as phenylsulfamoyl, diphenylsulfamoyl etc., mono- or di-C7-16 aralkylsulfamoyl group such as benzylsulfamoyl, dibenzylsulfamoyl etc., and the like), lower alkoxy-carbonyl group (e.g., C1-4 alkoxy-carbonyl group such as ethoxycarbonyl, ethoxycarbonyl, butoxycarbonyl etc., and the like), and the like.
Examples of the xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented by R1 include chain hydrocarbon group, cyclic hydrocarbon group and the like.
Examples of the xe2x80x9cchain hydrocarbon groupxe2x80x9d include linear or branched hydrocarbon groups having 1 to 10 carbon atoms, and the like, which is specifically alkyl group, alkenyl group, alkynyl group and the like. Of these, alkyl group is particularly preferable. Examples of the xe2x80x9calkyl groupxe2x80x9d include C1-10 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and the like, and the like, of which C1-6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl etc.) is preferable. Examples of the xe2x80x9calkenyl groupxe2x80x9d include C2-10 alkenyl groups such as vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyl and the like, and the like, of which C2-6 alkenyl group (e.g., vinyl, 1-propenyl, allyl etc.) is preferable. Examples of the xe2x80x9calkynyl groupxe2x80x9d include C2-10 alkynyl groups such as ethynyl, 1-propnyl, propargyl etc., and the like, of which C2-6 alkynyl group (e.g., ethynyl and the like) is preferable.
Examples of the xe2x80x9ccyclic hydrocarbon groupxe2x80x9d include cyclic hydrocarbon group having 3 to 18 carbon atoms, such as alicyclic hydrocarbon group, aromatic hydrocarbon group and, the like.
Examples of the xe2x80x9calicyclic hydrocarbon groupxe2x80x9d include monocyclic or fused polycyclic group consisting of 3 to 10 carbon atom, which is specifically cycloalkyl group, cycloalkenyl group and 2 or 3 cyclic fused ring of these and C6-14 aryl group (e.g., benzene etc.) and the like, and the like. Examples of the xe2x80x9ccycloalkyl groupxe2x80x9d include C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc., and the like, examples of the xe2x80x9ccycloalkenyl groupxe2x80x9d include C3-6 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl etc., and the like.
Examples of the xe2x80x9caromatic hydrocarbon groupxe2x80x9d include monocyclic aromatic hydrocarbon group consisting of 6 to 18 carbon atoms, fused polycyclic aromatic hydrocarbon group and the like, which is specifically C6-14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl and the like and C6-10 aryl group (e.g., phenyl etc.) and the like are preferable.
The substituent that the xe2x80x9cchain hydrocarbon groupxe2x80x9d in the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d may have is not particularly limited and examples thereof include halogen atom, hydroxy group, alkoxy group, acyloxy group, alkylthio group, acylamino group, carboxyl group, alkoxycarbonyl group, oxo group, alkanoyl group, cycloalkyl group, aryl group, aromatic heterocyclic group and the like. These substituents is substituted in the range chemically acceptable on the xe2x80x9cchain hydrocarbon groupxe2x80x9d wherein the number of the substituent is 1 to 5, preferably 1 to 3. When the number of the substituents is 2 or above, they may be the same or different.
Examples of the xe2x80x9chalogen atomxe2x80x9d include fluorine, chlorine, bromine, iodine and the like.
Examples of the xe2x80x9calkoxy groupxe2x80x9d include C1-10 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc., and the like. Examples of the xe2x80x9cacyloxy groupxe2x80x9d include formyloxy, C1-10 alkylcarbonyloxy group (e.g., acetoxy, propionyloxy etc.) and the like. Examples of the xe2x80x9calkylthio groupxe2x80x9d include C1-10 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio etc., and the like. Examples of the xe2x80x9cacylamino groupxe2x80x9d include formylamino, diformylamino, mono- or di-C1-10 alkylcarbonylamino group (e.g., acetylamino, propionylamino, butyrylamino, diacetylamino etc.) and the like. Examples of the xe2x80x9calkoxycarbonyl groupxe2x80x9d include C1-10 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl etc., and the like. Examples of the xe2x80x9calkanoyl groupxe2x80x9d include C1-10 alkylcarbonyl group such as acetyl, propionyl, butyryl, valeryl etc., and the like. Examples of the xe2x80x9ccycloalkyl groupxe2x80x9d include C3-10 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc., and the like. Examples of the xe2x80x9caryl groupxe2x80x9d include C6-14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl etc. , and the like. Examples of the xe2x80x9caromatic heterocyclic groupxe2x80x9d include 1 to 3 cyclic aromatic heterocyclic groups containing, besides carbon atom, preferably 1 to 4 of 1 or 2 kinds of heteroatom selected from nitrogen, oxygen and sulfur, and the like. Specific examples thereof include thienyl, pyridyl, furyl, pyrazinyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridazinyl, tetrazolyl, quinolyl, indolyl, isoindolyl and the like.
The substituent that the xe2x80x9ccyclic hydrocarbon groupxe2x80x9d in the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d may possess is not particularly limited. Examples thereof include halogen atom, hydroxy group, alkoxy group, acyloxy group, alkylthio group, alkylsulfonyl group, mono- or di-alkylamino group, acylamino group, carboxyl group, alkoxycarbonyl group, alkanoyl group, alkynylcarbonyl group, alkyl group, cycloalkyl group, aryl group, aromatic heterocyclic group and the like. These substituents are substituted on the xe2x80x9ccyclic hydrocarbon groupxe2x80x9d in a chemically acceptable range, wherein the number of the substituent is 1 to 5, preferably 1 to 3. When the number of substituents is 2 or above, they may be the same or different. Of these substituents, halogen atom, alkoxy group, acyloxy group, alkylthio group, acylamino group, alkoxycarbonyl group, alkanoyl group, cycloalkyl group, aryl group and aromatic heterocyclic group are similar to those defined above as the substituent on the xe2x80x9cchain hydrocarbon groupxe2x80x9d.
Examples of the xe2x80x9calkylsulfonyl groupxe2x80x9d include C1-10 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl etc., and the like. Examples of the xe2x80x9calkylamino groupxe2x80x9d include mono-C1-4 alkylamino groups such as methylamino, ethylamino, propylamino and the like, di-C1-4 alkylamino groups such as dimethylamino, diethylamino and the like, examples of the xe2x80x9calkynylcarbonyl groupxe2x80x9d include C3-10 alkynylcarbonyl groups such as ethynylcarbonyl, 1-propynylcarbonyl, 2-propynylcarbonyl etc., and the like. Example of the xe2x80x9calkyl groupxe2x80x9d include C1-10 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl etc., and the like.
The substituent that the aforementioned xe2x80x9chydrocarbon groupxe2x80x9d may have, in a chemically acceptable range, 1 to 5, preferably 1 to 3, substituents shown below. Examples of such substituent include halogen atom (e.g., fluorine, chlorine, bromine etc.), hydroxy group, C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy etc.), and the like.
Examples of the aromatic heteromonocyclic group of the xe2x80x9caromatic heteromonocyclic group optionally having substituentsxe2x80x9d represented by R1 include 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 3-pyridazinyl and the like. Of these, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-imidazolyl, 4-imidazolyl and the like are preferable.
The substituent of the xe2x80x9caromatic heteromonocyclic group optionally having substituentsxe2x80x9d represented by R1 may be substituted in the number of 1 to 3 at substitutable positions of the aromatic heteromonocyclic group. Examples of the substituent include alkyl group optionally substituted by 1 to 5 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), which is exemplified by C1-4 alkyl group such as methyl, ethyl, propyl etc. and C1-4 alkyl group substituted by halogen such as 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl etc., C1-3 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy etc., halogen atom such as chlorine atom, fluorine atom etc., hydroxy group, amino group, nitro group and the like.
Of the aforementioned examples, preferable as R1 are hydrogen atom, lower alkyl group (those having 1 to 4 carbon atoms) optionally having substituents, lower alkenyl group (those having 1 to 4 carbon atoms), cyclic alkyl group (those having 3 to 6 carbon atoms), phenyl group optionally having substituents and pyridyl group optionally having substituents. Of these, hydrogen atom, lower alkenyl group (those having 1 to 4 carbon atoms), cyclic alkyl group (those having 3 to 6 carbon atoms), phenyl group, pyridyl group and lower alkyl group (those having 1 to 4 carbon atoms) optionally having halogen as substituent are particularly preferable.
Examples of the lower alkyl group of R2 include chain or cyclic C1-6 alkyl group optionally having substituents (e.g., methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, hexyl etc.). The C1-6 alkyl group may have 1 to 5 substituents at substitutable positions and examples of the substituent include halogen (e.g., fluorine, chlorine, bromine, iodine), C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy etc.) and the like.
Preferable examples of R2 are, of the aforementioned, hydrogen atom and non-substituted lower alkyl group (those having 1 to 6 carbon atoms), particularly preferably hydrogen atom.
Examples of the xe2x80x9chydroxy group optionally having substituentsxe2x80x9d represented by R3, R4, R5, R6, R7, R8 and R9 include, besides non-substituted hydroxy group, lower alkoxy group (e.g., C1-4 alkoxy group such as methoxy, ethoxy, propoxy etc.), lower alkanoyloxy group (e.g., C1-4 alkanoyloxy such as acetyloxy, propionyloxy etc.), carbamoyloxy group optionally having substituents (e.g., non-substituted carbamoyloxy and carbamoyloxy substituted by 1 or 2 C1-4 alkyl groups such as, ethylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy, methylethylcarbamoyloxy etc.), and the like.
Examples of the xe2x80x9cthiol group optionally having substituentsxe2x80x9d represented by R3, R4, R5, R6, R7, R8 and R9 include, besides non-substituted thiol group, lower alkylthio group (e.g., C1-4 alkylthio group such as methylthio, ethylthio, propylthio etc.), lower alkanoylthio group (e.g., C1-4 alkanoylthio such as acetylthio, propionylthio etc.), and the like.
Examples of the xe2x80x9camino group optionally having substituentsxe2x80x9d represented by R3, R4, R5, R6, R7, R8 and R9 include, besides non-substituted amino group, lower alkylamino group (e.g., C1-4 alkylamino group such as methylamino, ethylamino, propylamino etc.), di-lower alkylamino group (e.g., di-C1-4 alkylamino such as dimethylamino, diethylamino etc.), C1-4 alkanoylamino group (e.g., acetamide, propionamide etc.), and the like.
Examples of the acyl group represented by R3, R4, R5, R6, R7, R8 and R9 include alkanoyl group (e.g., C1-6 alkanoyl such as formyl, acetyl, propionyl etc.), arylsulfonyl group (e.g., benzenesulfonyl, p-toluenesulfonyl etc.), carbamoyl group optionally having substituents (besides non-substituted carbamoyl group, mono- or di-C1-4 alkylcarbamoyl group such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl group etc., mono- or di-C6-14 arylcarbamoyl group such as phenylcarbamoyl, diphenylcarbamoyl group etc., mono- or di-C7-16 aralkylcarbamoyl group such as benzylcarbamoyl, dibenzylcarbamoyl etc.), alkylsulfonyl group (e.g., C1-4 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl etc.), sulfamoyl group optionally having substituents (e.g., mono- or di-C1-10 alkylsulfamoyl group such as methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl etc., mono- or di-C6-14 arylsulfamoyl group such as phenylsulfamoyl, diphenylsulfamoyl etc., mono- or di-C7-16 aralkylsulfamoyl group such as benzylsulfamoyl, dibenzylsulfamoyl etc., and the like), lower alkoxy-carbonyl group (e.g., C1-4 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl etc., and the like), and the like.
Examples of the halogen represented by R3, R4, R5, R6, R7, R8 and R9 include fluorine, chlorine, bromine and iodine.
Examples of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented by R3, R4, R5, R6, R7, R8 and R9 include those similar to the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented by R1. Of these, lower alkyl group optionally having substituents is preferable. Examples thereof include chain or cyclic C1-6 alkyl group optionally having substituents (e.g., methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, hexyl etc.). The C1-6 alkyl group may have 1 to 5 substituents at substitutable positions, and examples of the substituent include halogen (e.g., fluorine, chlorine, bromine, iodine), C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy etc.), hydroxy group, and the like. The C1-4 alkoxy group may have 1 to 5 substituents at substitutable positions, and examples of the substituent include halogen (e.g., fluorine, chlorine, bromine, iodine), C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy etc.), and the like.
Preferable examples of the R3, R4, R5, R6, R7, R8 and R9 include, of the aforementioned examples, hydrogen atom, hydrocarbon group optionally having substituents, hydroxy group optionally having substituents, amino group optionally having substituents, carbamoyl group optionally having substituents, C1-6 alkanoyl group and halogen atom.
Of R3, R4, R5, R6, R7, R8 and R9 R7 is preferably an optionally substituted hydroxy group or a lower alkyl group. It is preferably (1) hydroxy group optionally having, as a substituent, lower alkanoyl group, lower alkanoyloxy(lower)alkyl group, lower alkyl group, lower alkoxy(lower)alkyl group, lower alkyl group optionally substituted by 1 to 4 fluorine atoms or benzyl group, (2) halogen atom, (3) lower alkyl group optionally substituted by hydroxy group, (4) lower alkynyl group, (5) lower alkanoyl group, (6) amino group optionally having lower alkanoyl group, lower alkylaminocarbonyl group and lower alkylsulfonyl group as a substituent or (7) lower alkylthio group, more preferably lower alkyl group, lower alkoxy group, lower alkanoylamino group or lower alkylcarbamoyl group. R8 is preferably hydrogen atom, lower alkyl group or lower alkoxy group, more preferably hydrogen atom or lower alkoxy group. R6 is preferably (1) hydrogen atom, (2) halogen atom, (3) lower alkoxy group or (4) lower alkyl group optionally substituted by hydroxy group, more preferably hydrogen atom or lower alkyl group.
Examples of the combination of R3, R4, R5, R6, R7, R8 and R9 is that wherein 1 to 3 thereof are each preferably independently lower alkyl group optionally having substituents, hydroxy group optionally having substituents, amino group optionally having substituents, carbamoyl group optionally having substituents, C1-6 alkanoyl group or halogen atom.
It is preferable that any of R6, R7 and R8 is lower alkyl group, lower alkoxy group, lower alkanoylamino group or lower alkylcarbamoyl group, and that all of R3, R4, R5 and R9 are hydrogen atoms.
Of the compounds (I), a compound wherein R1 is C1-6 alkyl group and R2 is hydrogen atom.
When R7 is bonded with R6 or R8 and form, together with carbon atom on the naphthalene ring, a 5 or 6-membered ring containing oxygen atom, examples of the ring include furan ring, dihydrofuran ring, pyran ring, dihydropyran ring, dioxolen ring, oxazole ring, isoxazole ring and the like.
Preferable examples of the compound represented by the formula (I) include compounds of the formulas 
wherein each symbol is as defined above, and the like. Examples of the preferable compound include 1-(1H-imidazol-4-yl-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol, 1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol, 1-(6-methoxy-5-methylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol, N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamide and N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl-2-naphthamide.
In the aforementioned formulas, ring A may have 1 to 5, preferably 1 or 2 substituents at optional positions. Examples of the substituent include lower alkyl group optionally having substituents, hydroxy group optionally having substituents, thiol group optionally having substituents, nitro group, amino group optionally having substituents, acyl group, halogen atom, methylenedioxy group optionally having substituents (or adjacent two substituents are bonded) and the like.
Examples of the lower alkyl group of the xe2x80x9coptionally substituted lower alkyl groupxe2x80x9d include C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like. Examples of the substituent include halogen atom such as fluorine, chlorine, bromine and the like, C1-7 alkoxy group such as methoxy, ethoxy, propoxy, benzyloxy and the like, C1-7 alkylthio group such as methylthio, ethylthio, propiothio, benzylthio and the like, hydroxy group, and substituted amino group such as acetylamino, benzoylamino, methanesulfonylamino, benzenesulfonylamino and the like.
Examples of the hydroxy group optionally having substituents include, besides non-substituted hydroxy group, lower alkoxy group (e.g., linear or branched C1-6 alkoxy group such as methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, hexyloxy etc.), lower alkanoyloxy group (e.g., C1-4 alkanoyloxy such as acetyloxy, propionyloxy etc.), carbamoyloxy group optionally having substituents (e.g., non-substituted carbamoyloxy, carbamoyloxy substituted by 1 or 2 C1-4 alkyl groups such as methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy, methylethylcarbamoyloxy etc.) and the like.
Examples of the thiol group optionally having substituents include, besides non-substituted thiol group, lower alkylthio group (e.g., C1-4 alkylthio group such as methylthio, ethylthio, propylthio etc.), lower alkanoylthio group (e.g., C1-4 alkanoylthio such as acetylthio, propionylthio etc.) and the like.
Examples of the amino group optionally having substituents include, besides non-substituted amino group, lower alkylamino group (e.g., C1-4 alkylamino group such as methylamino, ethylamino, propylamino etc.), di-lower alkylamino group (e.g., di-C1-4 alkylamino such as dimethylamino, diethylamino etc.), C1-4 alkanoylamino group (e.g., acetamide, propionamide etc.) and the like.
Examples of the acyl group include alkanoyl group (e.g., C1-6 alkanoyl such as formyl, acetyl, propionyl etc.), alkylsulfonyl group (e.g., C1-4 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl etc.), arylsulfonyl group (e.g., benzenesulfonyl, p-toluenesulfonyl etc.), carbamoyl group optionally having substituents (e.g., mono- or di-C1-10 alkylcarbamoyl group such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl etc., mono- or di-C6-14 arylcarbamoyl such as phenylcarbamoyl, diphenylcarbamoyl etc., mono- or di-C7-16 aralkylcarbamoyl group such as benzylcarbamoyl, dibenzylcarbamoyl etc., and the like), sulfamoyl group optionally having substituents (e.g., mono- or di-C1-10 alkylsulfamoyl group such as methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl etc., mono- or di-C6-14 arylsulfamoyl group such as phenylsulfamoyl, diphenylsulfamoyl etc., mono- or di-C7-16 aralkylsulfamoyl group such as benzylsulfamoyl, dibenzylsulfamoyl etc., and the like), lower alkoxy-carbonyl group (e.g., C1-4 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl etc., and the like) and the like.
Examples of the halogen atom include fluorine, chlorine, bromine and iodine.
The methylenedioxy group optionally having substituents are substituted at the two adjacent carbons of the benzene ring, and examples thereof include, besides non-substituted methylenedioxy group, and said methylene group substituted by, for example, halogen (e.g., fluorine atom, chlorine atom, bromine atom, iodine), nitro group, hydroxy group, amino group and the like.
When ring A has a substituent, preferable examples thereof include halogen atom, alkyl group and alkoxy group. Particularly preferable examples of the ring A include non-substituted one and one having chlorine atom and/or methoxy group as substituent. The positions of substitution are 2-position, 4-position, and 2-, 4-positions.
As a preferable example of R10 and R11, a case where both and R12 are methyl groups and a case where R10 and R11 are bonded to show tetramethylene group are mentioned. Examples of the hydrocarbon group optionally having substituents, which is represented by R10 and R11, include, besides non-substituted C1-4 alkyl group such as methyl, ethyl, propyl and the like, these having substituents such as C2-5 alkanoyl such as acetyl, propionyl etc., carboxyl, C1-4 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl etc.) and the like, at optional positions and the like.
Examples of the halogen atom represented by R10 and R11 include fluorine atom, chlorine atom, bromine atom, iodine atom and the like.
When R10 and R11 in combination show an alkylene group optionally having substituents, examples of the xe2x80x9calkylene group optionally having substituentsxe2x80x9d include non-substituted alkylene having 2 to 5 carbon atoms (dimethylene, trimethylene, tetramethylene, pentamethylene), these alkylene having, at optional positions, substituents such as lower alkyl group (e.g., C1-4 alkyl such as methyl, ethyl, propyl etc.), lower alkoxy group (e.g., C1-4 alkoxy such as methoxy, ethoxy, propoxy etc.), hydroxy group, amino group, nitro group, halogen atom (e.g., fluorine, chlorine, bromine, iodine) and the like.
Examples of the lower alkyl group optionally having substituents, which is represented by R12, include, besides linear or branched non-substituted C1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc., such alkyl group substituted by C1-6 alkanoyl (e.g., acetyl, propionyl etc.), carboxyl, C1-4 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl etc.), and the like, and the like.
Examples of the aryl group optionally having substituents, which is represented by R12, include, besides aryl group having 6 to 10 carbon atoms such as non-substituted phenyl group, naphthyl group etc., such aryl group having substituents such as lower alkyl group (e.g., C1-4 alkyl such as methyl, ethyl, propyl etc.), lower alkoxy group (e.g., C1-4 alkoxy such as methoxy, ethoxy, propoxy etc.), hydroxy group, amino group, nitro group, halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine) and the like at optional positions.
As R12, methyl and ethyl are particularly preferable.
As the C2-4 alkylene optionally having substituents, which is represented by Alk, alkylene group optionally having substituents, which is formed by R10 and R11 in combination, wherein the alkylene moiety has 2 to 4 carbon atoms, is mentioned.
Ring B and ring C are each an aromatic ring optionally having substituents, which has 1 to 5, preferably 1 or 2, substituents at optional positions. Examples of the aromatic ring include benzene ring, naphthalene ring and the like and examples of the substituent include lower alkyl group, lower alkenyl group, lower alkoxy group, lower alkylthio group, halogen atom, cyano group and the like. Examples of the xe2x80x9clower alkyl groupxe2x80x9d include C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl group, examples of the xe2x80x9clower alkenyl groupxe2x80x9d include C2-6 alkenyl group such as vinyl, 1-propenyl, allyl, isopropenyl, butenyl etc., examples of the xe2x80x9clower alkoxy groupxe2x80x9d include C1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. Examples of the xe2x80x9clower alkylthio groupxe2x80x9d include C1-7 alkylthio group such as methylthio, ethylthio, propiothio, benzylthio etc. and examples of the halogen atom include chlorine, bromine and the like. Preferable examples of the ring B and ring C include, besides non-substituted naphthalene ring, naphthalene ring having methyl group and/or methoxy group as substituents.
Examples of the hydrocarbon group of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d, which is represented by R13 and R14, include aliphatic chain hydrocarbon group, alicyclic hydrocarbon group and the like.
Examples of the aliphatic chain hydrocarbon group include linear or branched aliphatic hydrocarbon such as alkyl group, alkenyl group, alkynyl group and the like. Examples of the alkyl group include C1-10 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl etc., and the like. It is preferably lower C1-6 alkyl group. Examples of the alkenyl group include C2-6 alkenyl groups such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 1-hexenyl etc., and the like. Examples of the alkynyl group include C2-6 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl etc., and the like.
Examples of the alicyclic hydrocarbon group include saturated or unsaturated alicyclic hydrocarbon groups such as cycloalkyl group, cycloalkenyl group, cycloalkanedienyl group and the like. Examples of the cycloalkyl group include C3-9 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, 1-adamantyl group etc., and the like. Examples of the cycloalkenyl group include C3-6 cycloalkenyl groups such as 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexan-1-yl, 3-cyclohexan-1-yl, 1-cyclobuten-1-yl etc., and the like. Examples of the cycloalkadienyl group include C4-6 cycloalkadienyl groups such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl etc., and the like.
Examples of the heterocyclic group of the xe2x80x9cheterocyclic s group optionally having substituentsxe2x80x9d, which is represented by R13 and R14, include aromatic heterocyclic group, saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and the like, which contain, as an atom constituting the ring (ring atom), at least 1 (preferably 1 to 4, more preferably 1 or 2) of 1 to 3 kinds (preferably 1 or 2 kinds) of heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like.
Examples of the xe2x80x9caromatic heterocyclic groupxe2x80x9d include 5 or 6-membered aromatic heteromonocyclic group such as aromatic heteromonocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl etc.) and the like and 8 to 12-membered aromatic fused heterocyclic group such as aromatic fused heterocyclic group (e.g., benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, a-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-b]pyridyl, imidazo[1,5-b]pyridyl, imidazo[1,2-a]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl etc.) and the like, with preference given to heterocyclic ring obtained by condensation of the aforementioned 5 to 6-membered aromatic heteromonocyclic group with benzene ring or heterocyclic ring obtained by condensation of the same or different two heterocyclic rings of the aforementioned 5 or 6-membered aromatic heteromonocyclic group) and the like.
Examples of the xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d include 3 to 8-membered (preferably 5 or 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl etc. and the like. As the substituent that the xe2x80x9cheterocyclic group optionally having substituentsxe2x80x9d as a substituent may have, lower alkyl group (e.g., C1-6 alkyl group such as methyl, ethyl, propyl etc., and the like), acyl group (e.g., C1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl etc., benzoyl and the like), and the like are mentioned.
Examples of the substituent of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d and xe2x80x9cheterocyclic group optionally having substituentsxe2x80x9d, which are represented by R13 or R14, include aryl group optionally having substituents, cycloalkyl group optionally having substituents, cycloalkenyl group optionally having substituents, alkyl group optionally having substituents, alkenyl group optionally having substituents, alkynyl group optionally having substituents, heterocyclic group optionally having substituents, amino group optionally having substituents, imidoyl group optionally having substituents, amidino group optionally having substituents, hydroxy group optionally having substituents, thiol group optionally having substituents, optionally esterified or amidated carboxyl group, thiocarbamoyl group optionally having substituents, halogen atom (e.g., fluorine, chlorine, bromine, iodine), cyano group, nitro group, acyl group derived from sulfonic acid, acyl group derived from carboxylic acid and the like, wherein the number of these optional substituents present at substitutable positions is 1 to 5, preferably 1 to 3.
Examples of the aryl group of the xe2x80x9caryl group optionally having substituentsxe2x80x9d as a substituent include C6-14 aryl group such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl etc., and the like. Examples of the substituent of the aryl group here include lower alkoxy group (e.g., C1-6 alkoxy group such as methoxy, ethoxy, propoxy etc., and the like), halogen atom (e.g., fluorine, chlorine, bromine, iodine), lower alkyl group (e.g., C1-6 alkyl group such as methyl, ethyl, propyl etc., and the like), amino group, hydroxy group, cyano group, amidino group and the like, wherein the number of these optional substituents present at substitutable positions is 1 or 2.
Examples of the cycloalkyl group of the xe2x80x9ccycloalkyl group optionally having substituentsxe2x80x9d as a substituent include C3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc., and the like. Examples of the substituent of the cycloalkyl group here include those similar in number and kind to the substituents of the aforementioned xe2x80x9caryl group optionally having substituentsxe2x80x9d.
Examples of the cycloalkenyl group of the xe2x80x9ccycloalkenyl group optionally having substituentsxe2x80x9d as a substituent include C3-6 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl etc., and the like. Examples of the substituent of the cycloalkenyl group optionally having substituents here include those similar in number and kind to the substituents of the aforementioned xe2x80x9caryl group optionally having substituentsxe2x80x9d.
Examples of the alkyl group of the xe2x80x9calkyl group optionally having substituentsxe2x80x9d as a substituent include C1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl etc., and the like. Examples of the substituent of the alkyl group include those similar in number and kind to the substituents of the aforementioned xe2x80x9caryl group optionally having substituentsxe2x80x9d.
Examples of the alkenyl group of the xe2x80x9calkenyl group optionally having substituentsxe2x80x9d as a substituent include C2-6 alkenyl group such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc., and the like. Examples of the substituent of the alkenyl group here include those similar in number and kind to the substituents of the aforementioned xe2x80x9caryl group optionally having substituentsxe2x80x9d.
Examples of the alkynyl group of the xe2x80x9calkynyl group optionally having substituentsxe2x80x9d as a substituent include C2-6 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. Examples of the substituents of the alkynyl group here include those similar in number and kind to the substituents of the aforementioned xe2x80x9caryl group optionally having substituentsxe2x80x9d.
Examples of the xe2x80x9cheterocyclic group optionally having substituentsxe2x80x9d as a substituent include those mentioned as the heterocyclic group of the xe2x80x9cheterocyclic group optionally having substituentsxe2x80x9d represented by R13 and R14, and examples of the substituent include alkyl group optionally substituted by 1 to 5 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), which is exemplified by C1-4 alkyl group such as methyl, ethyl, propyl etc., C1-4 alkyl group substituted by halogen, such as 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl and the like, C1-3 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy and the like, halogen atom such as chlorine atom, fluorine atom and the like, hydroxy group, amino group, nitro group and the like, which may be present in the number of 1 to 3 at substitutable positions of the heterocyclic group.
Examples of the substituent of the xe2x80x9camino group optionally having substituentsxe2x80x9d, xe2x80x9cimidoyl group optionally having substituentsxe2x80x9d, xe2x80x9camidino group optionally having substituentsxe2x80x9d, xe2x80x9chydroxy group optionally having substituentsxe2x80x9d and xe2x80x9cthiol group optionally having substituentsxe2x80x9d as substituents include lower alkyl group (e.g., C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl etc., and the like), acyl group (C1-6 alkanoyl (e.g., formyl, acetyl, propionyl, pivaloyl etc.), benzoyl etc.), optionally halogenated C1-6 alkoxy-carbonyl (e.g., trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl etc.) and the like. The xe2x80x9camino groupxe2x80x9d of the xe2x80x9camino group optionally having substituentsxe2x80x9d as a substituent may be substituted by imidoyl group optionally having substituents (e.g., C1-6 alkylimidoyl, formylimidoyl, amidino etc.) and the like, or two substituents, in combination with nitrogen atom, may form a cyclic amino group. In this case, examples of the cyclic amino group include 3 to 8-membered (preferably 5 or 6-membered) cyclic amino such as 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and 1-piperazinyl optionally having, at the 4-position, lower alkyl group (e.g., C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl etc., and the like), aralkyl group (e.g., C7-10 aralkyl group such as benzyl, phenethyl etc., and the like), aryl group (e.g., C6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl etc., and the like) and the like, and the like.
Examples of the xe2x80x9coptionally esterified carboxyl groupxe2x80x9d include, besides free carboxyl group, lower alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group and the like.
Examples of the xe2x80x9clower alkoxycarbonyl groupxe2x80x9d include C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl etc., and the like. Of these, C1-3 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl etc., and the like are preferable.
Preferable examples of the xe2x80x9caryloxycarbonyl groupxe2x80x9d include C7-12 aryloxy-carbonyl group such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl etc., and the like.
Preferable examples of the xe2x80x9caralkyloxycarbonyl groupxe2x80x9d include C7-10 aralkyloxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl etc., and the like (preferably C6-10 aryl-C1-4 alkoxycarbonyl etc.).
The xe2x80x9caryloxycarbonyl groupxe2x80x9d and xe2x80x9caralkyloxycarbonyl groupxe2x80x9d may have a substituent, and examples of the substituent include those similar in number and kind to the substituents of aryl group and aralkyl group as an example of the substituent of the N-monosubstituted carbamoyl group to be mentioned below.
The xe2x80x9clower alkoxycarbonyl groupxe2x80x9d here may have substituents, and examples of the substituent include those similar in number and kind to the substituents of the aforementioned xe2x80x9caryloxycarbonyl groupxe2x80x9d and xe2x80x9caralkyloxycarbonyl groupxe2x80x9d.
Examples of the substituent of the xe2x80x9cthiocarbamoyl group optionally having substituentsxe2x80x9d include those similar to the substituents of the xe2x80x9ccarbamoyl group optionally having substituentsxe2x80x9d to be mentioned below.
Examples of the xe2x80x9coptionally amidated carboxyl groupxe2x80x9d include carbamoyl group optionally having substituents, such as, besides non-substituted carbamoyl, N-monosubstituted carbamoyl group and N,N-disubstituted carbamoyl group.
The xe2x80x9cN-monosubstituted carbamoyl groupxe2x80x9d means a carbamoyl group having one substituent on a nitrogen atom. Examples of the substituent include lower alkyl group (e.g., C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl etc., and the like), cycloalkyl group (e.g., C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc., and the like), aryl group (e.g., C6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl etc., and the like), aralkyl group (e.g., C7-10 aralkyl group such as benzyl, phenethyl etc., preferably phenyl-C1-4 alkyl group and the like), heterocyclic group (e.g., those similar to the aforementioned xe2x80x9cheterocyclic groupxe2x80x9d as the substituent of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d, which is represented by R13, and the like) and the like. The lower alkyl group, cycloalkyl group, aryl group, aralkyl group and heterocyclic group may have a substituent, and examples of the substituent include hydroxy group, amino group optionally having substituents [said amino group optionally has, as a substituent, 1 or 2 from, for example, lower alkyl group (e.g., C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl etc., and the like), acyl group (e.g., C1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl etc., benzoyl and the like) and the like], halogen atom (e.g., fluorine, chlorine, bromine, iodine), nitro group, cyano group, lower alkyl group optionally substituted by 1 to 5 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), lower alkoxy group optionally substituted by 1 to 5 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), and the like.
Examples of the lower alkyl group include C1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc., and the like, particularly methyl, ethyl and the like are preferable. Examples of the lower alkoxy group include C1-6 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy etc., and the like, particularly preferably methoxy, ethoxy and the like. These substituents are the same or different and preferably present in the number of 1 or 2 or 3 (preferably 1 or 2).
The xe2x80x9cN,N-disubstituted carbamoyl groupxe2x80x9d means a carbamoyl group having 2 substituents on the nitrogen atom, wherein one of the substituents is exemplified by those similar to the substituent of the above-mentioned xe2x80x9cN-monosubstituted carbamoyl groupxe2x80x9d, and the other substituent is exemplified by lower alkyl group (e.g., C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl etc., and the like), C3-6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), C aralkyl group (e.g., benzyl, phenethyl etc., preferably phenyl-C1-4 alkyl group etc.) and the like. Two substituents may form a cyclic amino group together with a nitrogen atom, and examples of the cyclic aminocarbamoyl group in this case include 1-azetidinylcarbonyl, 1-pyrrolizinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl and 3 to 8-membered (preferably 5 or 6-membered) cyclic aminocarbonyl such as 1-piperazinylcarbonyl optionally having, at the 4-position, lower alkyl group (e.g., C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl etc., and the like), aralkyl group (e.g., C7-10 aralkyl group such as benzyl, phenethyl etc., and the like), aryl group (e.g., C6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl etc., and the like), and the like, and the like.
Examples of the xe2x80x9cacyl group derived from sulfonic acidxe2x80x9d as a substituent include one obtained by bonding the one substituent that the aforementioned xe2x80x9cN-monosubstituted carbamoyl groupxe2x80x9d has on the nitrogen atom to sulfonyl, and the like. Preferably, it is an acyl such as C1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.).
Examples of the xe2x80x9cacyl group derived from carboxylic acidxe2x80x9d as a substituent include one obtained by bonding hydrogen atom or the one substituent that the aforementioned xe2x80x9cN-monosubstituted carbamoyl groupxe2x80x9d has on the nitrogen atom to the carbonyl, and the like. Preferably, it is an acyl such as C1-6 alkanoyl (e.g., formyl, acetyl, propionyl, pivaloyl etc.), benzoyl and the like.
As R13 and R14, alkyl groups and cycloalkyl groups are preferable. Particularly preferably, a compound substituted by either tert-butyl or 1-adamantyl and methyl on the ring A of compound (V) is subjected to an asymmetric hydrogenation reaction. In addition, these groups may be substituted by the above-mentioned substituents. That is, a compound represented by the chemical formula: 
is preferable, particularly, a compound represented by 
is preferable.
Of the compounds represented by the formulas (IIa), (II), (V), (VI) and (VII), a compound having an acidic group or basic group may form a salt. When a compound has an acidic group, it may form a salt with, for example, a metal (e.g., sodium, potassium, calcium etc.) or an ammonium ion. When it has a basic group, the compound may form an acid addition salt, such as an inorganic acid salt (e.g., hydrochloride, sulfate, hydrobromate, phosphate etc.), an organic acid salt (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.) and the like.
Throughout the specification, of the compounds shown by the formulas (I), (IIa), (II), (V), (VI) and (VII), and salts thereof are referred to as compound (symbol of formula). For example, a compound of formula (I) and a salt thereof are sometimes simply referred to as compound (I).
According to the method of the present invention (1), compound (I) and an optically active form of compound (II) or (III) (hereinafter sometimes to be referred to as a resolution reagent) are reacted in a suitable solvent to give a diastereomer salt of compound (IVb) or (IVb). The compound (I) may be a racemate containing equivalent amounts of an (S)-compound and an (R)-compound, or a mixture containing either optical isomer in an amount exceeding the equivalent amount. The optically active form of compound (II) and (III) includes an (S)-compound and an (R)-compound.
The amount of the resolution reagent to be used is preferably 0.1-2 times, preferably 0.6-1.2 times, the mol amount relative to compound (I). In this case, mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid and the like, or organic acid such as acetic acid, propionic acid, fumaric acid, maleic acid and the like may be co-used with the resolution reagent to achieve said molar ratio. Two or more resolution reagents may be used simultaneously.
The solvent to be used is preferably one that dissolves compound (I) and resolution reagent, does not chemically change these compounds and in which one of the produced diastereomer salt is sparingly soluble. For example, water, alcohols such as methanol, ethanol, isopropanol etc., ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, tetrahydropyran etc., ketones such as acetone, 2-butanone etc., and nitriles such as acetonitrile etc., which may be used alone or in combination of two or more kinds thereof. The amount to be used is generally 1 to 100-fold amount, preferably 1 to 50-fold amount, relative to (I). The temperature is generally within the range of not less than 15xc2x0 C. and not higher than the boiling point of the solvent used.
After forming a diastereomer salt, cooling or concentration allows crystallization of either salt. Depending on the conditions, standing at room temperature without cooling or concentration may result in easy precipitation of a sparingly soluble salt.
The crystallized salt can be easily separated by a general solid-liquid separation method such as filtration, centrifugal separation and the like. The crystals of the separated salt can be made to have a high purity as necessary by a method known per se such as recrystallization and the like.
The mother liquor after separation of a sparingly soluble salt may contain, as it is, an easily soluble salt alone and as it is or may be cooled after concentration to separate an easily soluble salt.
The thus-obtained salt can be decomposed by any known method. For example, a treatment with an alkali or acid in a water-soluble solution achieves the object. Examples of the alkali include hydroxide of alkali metal or alkaline earth metal such as sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide and the like, alkali metal carbonate or hydrogen carbonate such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like, and organic base such as ammonia, pyridine and the like. Examples of the acid include mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid and the like, and organic acids such as trifluoroacetic acid, trifluoromethanesulfonic acid and the like. Generally, the salt can be treated with a water-soluble base such as aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, aqueous ammonia solution and the like and the liberated optically active naphthalene derivative is subjected to, for example, a solid-liquid separation such as filtration and centrifugal separation, or extraction step with an organic solvent and the like to give an optically active form of the objective compound (I). The treatment with a base is generally carried out at about xe2x88x9210 to 25xc2x0 C. and the amount of the base to be used is 1 to 5-fold molar amount relative to salt. The base concentration is 1-50 wt %, preferably 5-20 wt %.
When a basic aqueous layer after extraction of a naphthalene derivative is made acidic with an acid such as hydrochloric acid, sulfuric acid and the like, an optically active form of compound (II) or an optically active form of compound (III) used as a resolution reagent may be recovered and used again.
A naphthalene derivative represented by the formula (I), which is used as a starting material in the present invention, can be produced according to the method described in the following. 
wherein X1 is a halogen atom such as chlorine, bromine, iodine and the like, M is a metal atom (lithium, magnesium, metal halide such as magnesium chloride, magnesium bromide etc., and the like, L is a leaving group [C1-6-alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy etc.), C6-10 arylsulfonyloxy group (e.g., benzenesulfonyloxy, ortho-, meta-, or para-toluenesulfonyloxy, ortho-, meta-, or para-nitrobenzenesulfonyloxy and the like), R2a is a lower alkyl group optionally having substituents, Rxe2x80x2 is an optionally substituted nitrogen-containing heterocyclic group having a protecting group, and other symbols are as defined above.
The optionally substituted nitrogen-containing heterocyclic group of the xe2x80x9coptionally substituted nitrogen-containing heterocyclic group having a protecting groupxe2x80x9d represented by Rxe2x80x2 is the same as those represented by R above, and examples of the protecting group are as mentioned below.
The compound (IXa) is reacted with alkyl lithium, metal magnesium and the like to convert the compound to an organic metal compound (IXb), and then subsequently reacted with aldehyde compound (Xb) or (Xa) to give compound (XIa) or (XIb), respectively. Examples of the alkyl lithium to be used include C1-4 alkyl lithium such as n-butyl lithium, s-butyl lithium and the like. The amount of use thereof is 1 mol to 3-fold molar amount, preferably 1 to 1.5-fold molar amount, relative to 1 mol of the starting material compound (IXa). The reaction temperature at which alkyl lithium is reacted is from xe2x88x92100xc2x0 C. to 0xc2x0 C., preferably from xe2x88x9280xc2x0 C. to xe2x88x9220xc2x0 C. When metal magnesium is to be reacted, the reaction temperature is xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 10xc2x0 C. to 50xc2x0 C. The reaction time is from about 5 minutes to 20 hours. This reaction is generally carried out in an organic solvent inert to the reaction. Examples of the organic solvent that does not adversely affect the reaction include ethers such as diethyl ether, dioxane, tetrahydrofuran (THF) and the like, saturated hydrocarbons such as hexane, pentane and the like, halogenated hydrocarbons such as dichloromethane, chloroform and the like, aromatic hydrocarbons such as benzene, toluene and the like, and the like, which are used in admixture of one or more kinds thereof at a suitable mixing ratio. The aldehyde compound (Xb) or (Xa) is used in an amount of 0.5 equivalent amount to 10 equivalent amounts, preferably 0.5 to 1.5 equivalent amount, relative to compound (IXb).
The compound (XIa) and (XIb) are alkylated by a conventional method to give compound (XIc) and (Ia), respectively. The alkylation reagent (Xc) to be used is, for example, alkyl halide (e.g., methyl iodide, ethyl bromide, isopropyl bromide etc.), alkyl or arylsulfonic acid ester (e.g., methyl methanesulfonate, ethyl p-toluenesulfonate etc.) and the like. The amount of use thereof is 1 to 10 equivalent amount, preferably 1 to 2 equivalent amount, relative to compound (XIa) or (XIb). This reaction is generally carried out under basic conditions. Examples of the base to be used are sodium hydride, potassium carbonate, sodium methylate and the like. This reaction is generally carried out in a solvent inert to the reaction. Examples of such solvent include ethers such as dimethylformamide, tetrahydrofuran and the like, halogenated hydrocarbons such as dichloromethane and the like, and the like. While the reaction time varies depending on the activity and amount of alkylating agent, and base, it is generally from 30 minutes to 24 hours, preferably from 30 minutes to 10 hours. The reaction temperature is generally from xe2x88x9220xc2x0 C. to 150xc2x0 C.
The protecting group of R1a is removed from compound (XIc) by a method known per se or an analogous method to give compound (Ia). For example, when Rxe2x80x2 of compound (XIc) has a trityl group, or when a nitrogen-containing heterocyclic ring optionally having substituents is protected by a trityl group, the trityl group can be removed by a treatment under acidic conditions, or hydrogenolysis. Examples of the acid include organic acid such as formic acid, acetic acid and the like, inorganic acid such as hydrochloric acid etc., and the like. It is also possible to use a solvent inert to the reaction, such as alcohols, ethers such as THF etc., and the like. The reaction temperature is generally from 0xc2x0 C. to 100xc2x0 C. 
wherein R1b is as defined for R1 except hydrogen atom, and other symbols are as defined above.
The compound (XId) can be obtained by subjecting compound (XIa) to typical oxidization reaction. This reaction is generally carried out using manganese dioxide, chromic acid and the like as an oxidant, in a solvent inert to the reaction, such as dichloromethane, chloroform, THF and the like. The reaction time is generally from about 30 minutes to 48 hours, preferably from 30 minutes to 10 hours. The reaction temperature is generally from 0xc2x0 C. to 100xc2x0 C., preferably from 20xc2x0 C. to 70xc2x0 C.
The compound (XIe) can be obtained by removing the protecting group from compound (XId) by a method known per se or an analogous method. The protecting group can be removed according to the method analogous to the method to obtain compound (Ia) from compound (XIc). Then, compound (XIe) is reacted with an organic metal reagent (Xd) (alkyl lithium reagent such as methyllithium etc., Grignard""s reagent such as ethylmagnesium bromide, isopropyl magnesium chloride etc., and the like) to give compound (Ib). This reaction is generally carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Kouza Vol. 14, p. 512 (Maruzen) or a method analogous thereto. In this reaction, the organic metal reagent (Xd) is used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to the ketone compound (XIe). The reaction temperature is from xe2x88x92100xc2x0 C. to 50xc2x0 C., preferably from xe2x88x9280xc2x0 C. to 20xc2x0 C. The reaction time is from about 5 minutes to 20 hours. This reaction is carried out in an organic solvent generally inert to the reaction. Examples of the organic solvent that does not adversely affect the reaction include ethers such as diethyl ether, dioxane, tetrahydrofuran and the like, saturated hydrocarbons such as hexane, pentane and the like, halogenated hydrocarbons such as dichloromethane, chloroform and the like, aromatic hydrocarbons such as benzene, toluene and the like, and the like, which may be used alone or in combination of 2 or more kinds thereof.
The compound (Ib) can be also synthesized by reacting compound (XId) with compound (Xd) to give compound (XIf), which is followed by deprotection. 
wherein R0 is a group represented by ORxe2x80x3 or NRxe2x80x3Rxe2x80x2xe2x80x3 (Rxe2x80x3 and Rxe2x80x2xe2x80x3 are each C1-6 alkyl group, or C1-6 alkyloxy group and NRxe2x80x3Rxe2x80x2xe2x80x3 includes cyclic amine residue such as morpholino group, pyrrolidino group and the like), R1a is a nitrogen-containing heterocyclic group optionally having substituents, which may have protecting group, and other symbols are as defined above.
Of the above-mentioned nitrogen-containing heterocyclic group optionally having substituents and protecting group, which is represented by R1a, the group having a protecting group is the same as those mentioned with regard to the aforementioned Rxe2x80x2, and the group not having a protecting group is the same as those mentioned with regard to the aforementioned R.
The compound (XIg) and compound (Xe) are reacted according to Friedel-Crafts reaction known per se, for example, the method described in Shin Jikken Kagaku Kouza Vol. 14, p. 511 (Maruzen) or a method analogous thereto to give carbonyl compound (XIh). The compound (XIh) can be also synthesized by reacting compound (XIj) with compound (Xg). In this reaction, a solvent inert to the reaction, such as THF, dichloromethane and the like, is used and the compound (XIj) is used in an amount of 0.2-2 equivalents, preferably 0.2-1.5 equivalents, relative to compound (Xg). The reaction temperature is from xe2x88x9280xc2x0 C. to 50xc2x0 C., preferably from xe2x88x9280xc2x0 C. to 20xc2x0 C.
The compound (XIh) is alkylated using compound (Xf) to give compound (XIf). This reaction can be carried out according to the reaction to synthesize compound (Ib) from compound (XIe).
When organic metal reagent (IXb) is reacted with ketone compound (Xh) according to a method analogous to the method for synthesizing compound (Ib) from compound (XIe), compound (XIf) can be synthesized. When the nitrogen-containing heterocyclic ring of compound (XIf) is protected, the protecting group is removed according to a method analogous to the method for synthesizing compound (Ia) to give compound (Ib). 
wherein each symbol in the formula is as defined above.
The compound (XIf) is alkylated with (Xc) to give compound (XIk) and the protecting group is removed to give compound (Ic). The alkylation can be carried out according to a method analogous to the method for synthesizing compound (XIc) from compound (XIb). The protecting group can be removed according to a method analogous to the method for synthesizing compound (Ia) from compound (XIc).
Both the (S)-compound and (R)-compound of the optically active compound represented by the formula (II) can be produced according to a known method, such as the method described in The Journal of Organic Chemistry, Vol. 50, pp. 4508-4541 (1985).
The optically active compound represented by the formula (III) can be prepared according to a known method, such as the method described in JP-B-55-47013.
An optically active form of the compound (I) has a superior effect as a pharmaceutical agent, and especially has a superior inhibitory activity against steroid C17,20-lyase. The compound (I) is low toxic and causes few side effects. Therefore, compound (I) is useful as, for example, an agent for the prophylaxis or treatment of various diseases, such as (1) primary cancer of malignant tumor (e.g., prostate cancer, breast cancer, uterine cancer, ovarian cancer etc.), and metastasis or recurrence thereof, (2) various symptoms accompany these cancers (e.g., pain, cachexia etc.), (3) prostatic hypertrophy, virilism, hirsutism, male pattern alopecia, precocious puberty, endometriosis, uterus myoma, adenomyosis of uterus, mastopathy, polycystic ovary syndrome etc. in a mammal (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat etc., especially human).
While an optically active form of compound (I) has a superior effect even when used solely, the effect can be further promoted by using the compound in combination with other pharmaceutical preparations and therapies. Examples of the preparation and therapy to be combined include, but are not limited to, sex hormones, alkylating agents, antimetabolites, antitumor antibiotics, plant alkaloids, immunotherapies and the like.
Examples of other therapy include operation, thermotherapy, radiotherapy and the like.
Together with the chemotherapy including administration of compound (I), therapies other than chemotherapies, such as an operation including orchidectomy, thermotherapy, radiotherapy and the like can be conducted.
Examples of the pharmaceutically acceptable carrier include various organic or inorganic carriers conventionally used as materials for pharmaceuticals, which are added in suitable amounts as excipients, lubricants, binders, disintegrators, thickeners for solid preparations; solvents, dispersants, solubilizing agents, suspending agents, isotonic agents, buffer agents, soothing agents for liquid preparations, and the like. Where necessary, additives such as preservatives, antioxidants, coloring agents, sweetening agents etc. can be used. Examples of preferable excipient include lactose, saccharose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Examples of preferable lubricant include magnesium stearate, calcium stearate, talc, colloidal silica, and the like. Examples of preferable binder include crystalline cellulose, saccharose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, and the like. Examples of preferable disintegrator include starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium crosscarmellose, sodium carboxymethyl starch, and the like. Examples of preferable thickener include natural rubbers, cellulose derivatives, acrylate polymers, and the like. Examples of preferable solvent include water for injection, alcohol, propylene glycol, Macrogol, sesame oil, corn oil, and the like. Examples of preferable dispersant include Tween 80, HCO 60, polyethylene glycol, carboxymethylcellulose, sodium alginate, and the like. Examples of preferable solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like. Examples of preferable suspending agent include surfactants, such as stearyl triethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate etc.; hydrophilic polymer such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose etc.; and the like. Examples of preferable isotonic agent include sodium chloride, glycerin, D-mannitol and the like.
Examples of preferable buffer agent include buffer solution such as phosphate, acetate, carbonate, citrate etc., and the like. Examples of preferable soothing agent include benzyl alcohol, and the like. Examples of preferable preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Examples of preferable antioxidant include sulfurous acid salt, ascorbic acid, and the like.
The pharmaceutical preparation of the present invention can be manufactured by a conventional method. The ratio of compound (I) contained in a pharmaceutical preparation is usually 0.1 to 100% (w/w). Specific examples are shown below.
(1) Tablets, Powder, Granules, Capsules:
These can be produced by adding, for example, excipients, disintegrators, binders, lubricants etc. to compound (I), compression forming the mixture and, where necessary, coating for masking of taste, enteric or sustained release.
(2) Injection:
This can be produced by preparing compound (I) into an aqueous injection together with, for example, dispersants, preservatives, isotonic agents etc., or into an oily injection by dissolving, suspending or emulsifying the compound in a vegetable oil such as olive oil, sesame oil, cotton seed oil, corn oil etc., or propylene glycol etc.
The content of compound (I) admixed in these preparations is usually 0.01 to 50%, though subject to change depending upon the kind of preparations.
While the amount of compound (I) to be contained in the above-mentioned pharmaceutical preparation varies depending upon the compound selected, the kind of animal to be the administration target, administration frequency and the like, the compound proves effective over a broad range. The daily dose of the pharmaceutical preparation of the present invention as an effective amount of compound (I) of the present invention, for example, for in the case of oral administration to an adult patient with a solid tumor (e.g., patient with prostate cancer) is generally about 0.001 to about 500 mg/kg body weight, preferably about 0.1 to about 40 mg/kg body weight, more preferably about 0.5 to about 20 mg/kg body weight. When the compound is parenterally administered or administered concurrently with a different anticancer agent, the dose generally becomes less than those mentioned above. The amount of the compound actually administered is determined according to the selection of compound, dosage form of each preparation, age, body weight and sex of patient, degree of disease, administration route, period and intervals of administration and the like, which can be varied according to the judgment of a doctor.
The administration route of the aforementioned pharmaceutical preparation is free of any particular limitation by various conditions. The preparation can be administered, for example, orally or parenterally. Examples of the xe2x80x9cparenteralxe2x80x9d used here include intravenous, intramuscular, subcutaneous, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal and intraperitoneal administrations, and the like.
The above-mentioned administration term and administration interval vary depending upon various conditions and determined any time by judgment of a doctor. Divided administration, consecutive administration, intermittent administration, high dose short period administration, repeat administration and the like can be employed. For oral administration, for example, the dose is desirably given once a day or divided into several portions (especially two or three doses a day) and administered. Administration of a sustained release preparation or intravenous drip infusion over a long time is also possible.
The compound (IIa) can be produced according to the methods shown in the following Production method 1, Production method 2 and Production method 3. The starting material compound and synthetic intermediate can be subjected to a reaction in the form of a free compound or a salt like compound (IIa), or as a reaction mixture, or after isolation according to a known method.
First, compound (V) is subjected to asymmetric hydrogenation reaction to give an optically active form, which is then reduced and the obtained compound (VII) is subjected to phosphorylation to give the objective compound.
Production of compound (VI) by asymmetric hydrogenation of compound (V) is performed by hydrogenation in the presence of a complex of an optically active ligand and ruthenium.
A preferable embodiment usable as the optically active ligand in this reaction is bidentate phosphine. As a specific example thereof, structural formulas of one of the optical isomers are shown. 
wherein each symbol is as defined above.
Preferably, it is compound (VI) abbreviated as BisP*.
The compound (VIII) exemplified in the above formulas can be produced according to the method described in Journal of the American Chemical Society, Vol. 117, p. 4423 (1995).
For example, the ruthenium complex of compound (VIII) can be obtained by heating compound (VIII) and, for example, 1,5-cyclooctadieneruthenium (2-methylallyl) and the like, in a solvent such as hexane, filtration and concentration to give a solid, which is dissolved again in acetone and the like and treated with hydrobromic acid and the like.
In this reaction, the use of a ruthenium complex of compound (VIII) is preferable. As long as an optically active hydroxy compound can be produced from a keto compound, however, a complex with a transition metal other than ruthenium can be used.
This reaction is carried out generally under pressurization with a hydrogen gas. The hydrogen pressure is generally applied at 0.1 to about 100 kg/cm2, preferably about 1 to about 10 kg/cm2. This-reaction is preferably carried out in a solvent. The solvent may be any as long as it does not inhibit the reaction and is exemplified by hydrocarbons such as hexane, pentane and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like, aromatic hydrocarbons such as benzene, toluene and the like, aliphatic esters such as ethyl acetate, propyl acetate and the like, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and the like, halogenated hydrocarbons such as dichloromethane, chloroform and the like, alcohols such as methanol, ethanol, 2-propanol and the like, sulfoxides such as dimethyl sulfoxide and the like, nitriles such as acetonitrile and the like, water and the like. These solvents can be used alone or as a mixed solvent. Particularly preferably, a mixed solvent of methanol and water is used. The amount of the solvent to be used is generally about 1 to about 1000-fold volume, preferably about 5 to about 100-fold volume, relative to compound (V). The reaction temperature is about 0 to about 200xc2x0 C., preferably about 10 to about 100xc2x0 C. The reaction time is from about 10 minutes to about 100 hours, preferably from about 1 hour to about 50 hours. The amount of the ruthenium complex of compound (Xi) to be used is generally about 1/1 to about 1/100,000-fold mol, preferably about 1/10 to about 1/10,000-fold mol, relative to compound (V). The compound (VI) thus obtained can be isolated and purified by a method known per se, such as extraction, pH adjustment, phase transfer, salting-out, crystallization, chromatography and the like. It is also possible to subject the compound as a crude product in the next step.
The compound (VI) can be converted to compound (VII) by reduction. This reaction is carried out according to a method known per se.
The reducing agent includes, for example, metal hydrides such as sodium borohydride, lithium borohydride, lithium aluminum hydride, diisopropyl aluminum hydride, triethyl lithium borohydride and the like, diborane, 9-BBN, catechol borane and the like. The solvent includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as diethyl ether, diisopropyl ether, butylmethyl ether, dioxane, tetrahydrofuran and the like, halogenated hydrocarbons such as chloroform, dichloromethane, ethylene dichloride, carbon tetrachloride and the like, and the like. Depending on the kind of reducing agent, alcohols such as methanol, ethanol, propanol, butanol and the like can be used. Of these, ethers such as diethyl ether, tetrahydrofuran and the like are particularly preferable. These reducing agents are preferably used in an amount of 0.25-10 molar equivalents relative to compound (VI). Preferably, this reaction is generally carried out from xe2x88x9220 to 100xc2x0 C., more preferably from 0 to 100xc2x0 C., for 0.5 hour to 50 hours, preferably from 0.5 hour to 24 hours. The compound (VIII) thus obtained can be isolated by separation and purification means known per se, such as concentration, solvent extraction, crystallization, phase transfer, chromatography and the like.
The compound (VII) can be advantageously converted to compound (IIa) by, for example, reaction with phosphoryl chloride, and then alkaline hydrolysis, and neutralization with an acid, as shown in the following formulas. 
wherein each symbol is as defined above.
The amount of phosphoryl chloride to be used is 1-5 molar equivalents, preferably 1-2 molar equivalents, relative to compound (VII). The solvent includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as diethyl ether, diisopropyl ether, butylmethyl ether, dioxane, tetrahydrofuran and the like, halogenated hydrocarbons such as chloroform, dichloromethane, ethylene dichloride, carbon tetrachloride and the like, and the like. Particularly preferably, halogenated hydrocarbons such as dichloromethane and the like are used. This reaction is carried out at generally from 0 to 150xc2x0 C., preferably from 20 to 100xc2x0 C., for 0.5 hour to 50 hours, preferably from 0.5 hour to 10 hours. The chlorides of phosphoric acid thus obtained can be isolated by a separation and purification means known per se, such as concentration, solvent extraction, crystallization, phase transfer, chromatography and the like. It is also possible to subject the compound to the next hydrolysis step as a crude product. The hydrolysis is carried out in the presence of a base, preferably alkali metal hydroxide, sodium hydroxide, potassium hydroxide and the like. The amount of the base to be used is 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (VII). The solvent includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as diethyl ether, diisopropyl ether, butylmethyl ether, dioxane, tetrahydrofuran and the like, halogenated hydrocarbons such as chloroform, dichloromethane, ethylene dichloride, carbon tetrachloride and the like, alcohols such as methanol, ethanol and the like, water and the like. Particularly preferably, it is water. These may be used alone or as a mixed solvent. This reaction is carried out generally from 0xc2x0 C. to 200xc2x0 C., preferably from 50xc2x0 C. to 150xc2x0 C., for 0.1 hour to 50 hours, preferably from 0.1 hour to 2 hours.
Neutralization can be performed by adding an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like. The compound (IIa) thus obtained can be isolated according to a separation and purification means known per se, such as concentration, solvent extraction, crystallization, phase transfer, chromatography and the like.
When, of the compounds (V), R10 and R11 in combination show an alkylene group optionally having substituents, these compounds can be produced by, as shown in the following formula, reacting compound (Vxe2x80x2) wherein both R10 and R11 are hydrogen atoms with compound (Xi) to cycloalkylate the alpha-position carbon of the beta-ketoester.
As shown below 
wherein X1 and X2 are the same or different and each is a halogen atom, C1-6 alkylsulfonyloxy group or C6-10 arylsulfonyloxy group, and other symbols are as defined above, the compound can be produced by cycloalkylating the alpha-position carbon of the beta-ketoester according to a method known per se.
In the above-mentioned formulas, halogen atom represented by X2 is exemplified by chlorine, bromine and iodine, C1-6 alkylsulfonyloxy group is exemplified by methylsulfonyloxy, ethylsulfonyloxy and the like , and C6-10 arylsulfonyloxy group is exemplified by benzenesulfonyloxy, ortho-, meta-, or para-toluenesulfonyloxy, ortho-, meta-, or para-nitrobenzenesulfonyloxy group and the like.
Using compound (V) as a starting material, the series of the following reactions are carried out to synthesize racemate compound (IIa), which is optically resolved to advantageously give the compound. 
wherein each symbol is as defined above.
That is, compound (V) is reduced to give a diol compound, which is then subjected to phosphorylation to give racemate compound (IIxe2x80x2), which is then subjected to optical resolution to give an optically active isomer.
The first step of this production method is performed according to a method known per se. The reducing agent is exemplified by metal hydrides such as sodium borohydride, lithium borohydride, lithium aluminum hydride, diisopropyl aluminum hydride, triethyl lithium borohydride and the like, and boranes such as diborane, catecholborane, 9-BBN and the like. The solvent is exemplified by aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as diethyl ether, diisopropyl ether, butylmethyl ether, dioxane, tetrahydrofuran and the like, and halogenated hydrocarbons such as chloroform, dichloromethane, ethylene dichloride, carbon tetrachloride and the like. Alcohols such as methanol, ethanol, propanol and the like may be used in some cases. Preferably, ethers such as diethyl ether, tetrahydrofuran and the like are used. These reducing agents are use in amount of 0.5-10 molar equivalents, preferably 0.5-2 molar equivalents, relative to compound (V). This reaction is generally carried out from xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably from 0xc2x0 C. to 100xc2x0 C., for 0.5 hour to 100 hours, preferably from 0.1 hour to 24 hours. The diol compound thus obtained can be isolated by a separation and purification means known per se, such as concentration, solvent extraction, crystallization, phase transfer and chromatography. It is also possible to use the compound as a crude product as a starting material for the next step.
The phosphorylation step of compound (VII) can be carried out in the same manner as in phosphorylation of the aforementioned compound (VII).
The next step is optical resolution. The optical resolution of the obtained racemate cyclic phosphoric acid (dioxaphosphorinan) can be carried out by liquid chromatography using an optically active column, or by introducing into a diastereomer by the reaction with an optically active alcohol and separation by physical means, or by forming a diastereomer salt by reaction with an optically active amino compound and separation by physical means. Of these, a method for forming a diastereomer salt as shown in the following formulas is particularly preferable. 
wherein each symbol is as defined above.
The optically active amino compound used to form a diastereomer salt cannot be specified because it varies depending on compound (IIa) and each compound. For example, it includes (xe2x88x92)-ephedrine, (+)-cinchonine, (xe2x88x92)-cinchonine, (+)-quinidine, (xe2x88x92)-quinidine, (+)-dehydroabiethylamine, (+)-2-amino-1-phenyl-1,3-propanediol, (xe2x88x92)-2-amino-1-phenyl-1,3-propanediol, (xe2x88x92)-(parahydroxyphenyl)glycine, (+)-phenylethylamine, (xe2x88x92)-phenylethylamine, (+)-tolylethylamine, (xe2x88x92)-tolylethylamine, (+)-(1-naphthyl)ethylamine, (+)-cyclohexylethylamine, (xe2x88x92)-cyclohexylethylamine, (+)-prolinol, and amino acid ester.
For mutual separation of diastereomer salts, crystallization and subsequent filtration are generally used, wherein each salt is obtained from crystals and mother liquor.
The salt obtained as crystals and the salt obtained by concentration of the mother liquor are each independently treated with acid to give an optically active compound (IIa). The acid to be used for this purpose includes, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like, with preference given to hydrochloric acid. This reaction is preferably carried out in a solvent, more preferably in water.
To improve the chemical purity or optical purity of the obtained compound (IIa), recrystallization can be performed.
Moreover, compound (IIa) can be advantageously produced according to, for example, the method described in Journal of Organic Chemistry, Vol. 50, p. 4508 (1985) and using aldehyde as a starting material by the following series of reactions to synthesize a racemate compound (IIa), which is then subjected to optical resolution. 
wherein each symbol is as defined above.
That is, by Aldol Canizzaro reaction of aromatic aldehyde and cycloalkylaldehyde to give a diol compound, which is then subjected to phosphorylation to give a racemate compound (IIa), followed by optical resolution thereof, an optically active isomer can be produced.
The first step in this Production method 3 is an Aldol Canizzaro reaction of aromatic aldehyde and cycloalkylaldehyde generally using 2 molar equivalents of cycloalkylaldehyde relative to aromatic aldehyde. This reaction is carried out as appropriate in a solvent in the presence of a base.
The base is exemplified by alkali metal alkoxides such as sodium methoxide, sodium ethoxide and the like, inorganic bases such as potassium carbonate, sodium carbonate and the like, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like, alkali metal hydrides such as sodium hydride, potassium hydride and the like, alkali metal carboxylates such as sodium acetate and the like, secondary amines such as piperidine, piperazine, pyrrolidine, morpholine, diethylamine and the like, and pyridines such as pyridine, dimethylaminopyridine and the like. Preferably, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like are used. The amount of these bases to be used is preferably 1 to 5 molar equivalents relative to aromatic aldehyde.
The solvent is exemplified by alcohols such as methanol, ethanol, propanol, butanol and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as diethyl ether, diisopropyl ether, butylmethyl ether, dioxane, tetrahydrofuran and the like, halogenated hydrocarbons such as chloroform, dichloromethane, ethylene dichloride, carbon tetrachloride and the like, N,N-dimethylformamide, dimethyl sulfoxide and the like. Preferably, alcohols such as methanol, ethanol and the like are used. The amount of the solvent to be used is 1 to 50-fold (v/w), preferably 1 to 10-fold (v/w), relative to aromatic aldehyde.
This reaction is generally carried out from 0xc2x0 C. to 100xc2x0 C., preferably from 0xc2x0 C. to 100xc2x0 C., for 0.5 hour to 50 hours, preferably for 0.5 hour to 24 hours.
The compound (VIIa) thus obtained can be isolated by a separation and purification means known per se, such as concentration, solvent extraction, crystallization, phase transfer, chromatography and the like. Alternatively, the compound can be used in the next step as a crude product.
The obtained diol compound can be converted to an optically active form (dioxaphosphorinan) or a compound represented by compound (IIa) according to the method described in the above-mentioned Production method 2.
An optically active form of compound (II) of the present invention resolves optically active isomers of various amino compounds, which are useful for the production of pharmaceutical agents, agricultural chemicals, liquid crystals and a starting material thereof and the like, and can be used as a reagent for optical resolution. For example, as described in Examples 2 and 8, the compound can be used as a reagent for optical resolution of 1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol, and 1-(1H-imidazol-4-yl-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol.